tbuckley/cabot-search huggingface dataset:
MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors
Authors: Dana C. Borcherding, Neha V. Amin, Kevin He, Xiaochun Zhang, Yang Lyu, Carina Dehner, Himanshi Bhatia, Angad Gothra, Layla Daud, Peter Ruminski, Christine A. Pratilas, Kai Pollard, Taylor Sundby, Brigitte C. Widemann, Angela C. Hirbe
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. Experimental Design: The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. Results: Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor–treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. Conclusions: These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.
Artificial intelligence-enabled screening strategy for drug repurposing in monoclonal gammopathy of undetermined significance
Authors: Alexander J. Ryu, Shaji Kumar, Angela Dispenzieri, Robert A. Kyle, S. Vincent Rajkumar, Thomas C. Kingsley
Journal: Blood Cancer Journal (2023)

Monoclonal gammopathy of undetermined significance (MGUS) is a benign hematological condition with the potential to progress to malignant conditions including multiple myeloma and Waldenstrom macroglobulinemia. Medications that modify progression risk have yet to be identified. To investigate, we leveraged machine-learning and electronic health record (EHR) data to screen for drug repurposing candidates. We extracted clinical and laboratory data from a manually curated MGUS database, containing 16,752 MGUS patients diagnosed from January 1, 2000 through December 31, 2021, prospectively maintained at Mayo Clinic. We merged this with comorbidity and medication data from the EHR. Medications were mapped to 21 drug classes of interest. The XGBoost module was then used to train a primary Cox survival model; sensitivity analyses were also performed limiting the study group to those with non-IgM MGUS and those with M-spikes >0.3 g/dl. The impact of explanatory features was quantified as hazard ratios after generating distributions using bootstrapping. Medication data were available for 12,253 patients; those without medications data were excluded. Our model achieved a good fit of the data with inverse probability of censoring weights concordance index of 0.883. The presence of multivitamins, immunosuppression, non-coronary NSAIDS, proton pump inhibitors, vitamin D supplementation, opioids, statins and beta-blockers were associated with significantly lower hazard ratio for MGUS progression in our primary model; multivitamins and non-coronary NSAIDs remained significant across both sensitivity analyses. This work could inform subsequent prospective studies, or similar studies in other disease states.
Cholera outbreak in Balochistan amidst flash floods: an impending public health crisis
Authors: Shizra Jawed, Muhammad Bilal Islam, Hashir Ali Awan, Irfan Ullah, Muhammad Sohaib Asghar
Journal: International Journal of Surgery (2023)

Despite being the largest province in Pakistan due to inadequate and underdeveloped infrastructure, Balochistan has been the worst-inflicted region with biblical floods. Following these disastrous flash floods, a sudden rise in cholera cases was seen in the affected province. To overcome this public health crisis, the authorities must put in place a system to ensure food safety, an adequate supply of clean drinking water, and the provision of proper sanitation facilities for the locals.
68Ga-FAPI-04 PET/CT in a Small Sarcomatoid Renal Cell Carcinoma With Widespread Metastases
Authors: Aisheng Dong, Bo Yang, Yushu Bai, Changjing Zuo
Journal: Clinical Nuclear Medicine (2023)

Sarcomatoid renal cell carcinoma is an uncommon high-grade malignancy with poor prognosis. We describe 68 Ga-FAPI-04 PET/CT findings in a patient with a small (1.8 cm in the maximum diameter) sarcomatoid clear cell renal cell carcinoma with widespread metastatic disease. Both the primary renal tumor and its metastases in bones, lymph nodes, adrenals, and liver showed increased 68 Ga-FAPI-04 uptake. The primary renal tumor showed hypovascularity on contrast-enhanced CT, mimicking papillary renal cell carcinoma. This case indicates FAPI PET/CT may be useful for detecting and staging of this unusual malignancy.
The fecal microbiotas of women of Pacific and New Zealand European ethnicities are characterized by distinctive enterotypes that reflect dietary intakes and fecal water content
Authors: Nikki Renall, Blair Lawley, Tommi Vatanen, Benedikt Merz, Jeroen Douwes, Marine Corbin, Lisa Te Morenga, Rozanne Kruger, Bernhard H Breier, Gerald W Tannock
Journal: Gut Microbes (2023)

Obesity is a complex, multifactorial condition that is an important risk factor for noncommunicable diseases including cardiovascular disease and type 2 diabetes. While prevention and management require a healthy and energy balanced diet and adequate physical activity, the taxonomic composition and functional attributes of the colonic microbiota may have a supplementary role in the development of obesity. The taxonomic composition and metabolic capacity of the fecal microbiota of 286 women, resident in Auckland New Zealand, was determined by metagenomic analysis. Associations with BMI (obese, nonobese), body fat composition, and ethnicity (Pacific, n = 125; NZ European women [NZE], n = 161) were assessed using regression analyses. The fecal microbiotas were characterized by the presence of three distinctive enterotypes, with enterotype 1 represented in both Pacific and NZE women (39 and 61%, respectively), enterotype 2 mainly in Pacific women (84 and 16%) and enterotype 3 mainly in NZE women (13 and 87%). Enterotype 1 was characterized mainly by the relative abundances of butyrate producing species, Eubacterium rectale and Faecalibacterium prausnitzii, enterotype 2 by the relative abundances of lactic acid producing species, Bifidobacterium adolescentis, Bifidobacterium bifidum, and Lactobacillus ruminis, and enterotype 3 by the relative abundances of Subdoligranulum sp., Akkermansia muciniphila, Ruminococcus bromii, and Methanobrevibacter smithii. Enterotypes were also associated with BMI, visceral fat %, and blood cholesterol. Habitual food group intake was estimated using a 5 day nonconsecutive estimated food record and a 30 day, 220 item semi-quantitative Food Frequency Questionnaire. Higher intake of 'egg' and 'dairy' products was associated with enterotype 3, whereas 'non-starchy vegetables', 'nuts and seeds' and 'plant-based fats' were positively associated with enterotype 1. In contrast, these same food groups were inversely associated with enterotype 2. Fecal water content, as a proxy for stool consistency/colonic transit time, was associated with microbiota taxonomic composition and gene pools reflective of particular bacterial biochemical pathways. The fecal microbiotas of women of Pacific and New Zealand European ethnicities are characterized by distinctive enterotypes, most likely due to differential dietary intake and fecal consistency/colonic transit time. These parameters need to be considered in future analyses of human fecal microbiotas.
Cognitive pragmatics: Insights from homesign conversations
Authors: Connie de Vos
Journal: Behavioral and Brain Sciences (2023)

Abstract Homesign is a visual–gestural form of communication that emerges between deaf individuals and their hearing interlocutors in the absence of a conventional sign language. I argue here that homesign conversations form a perfect testcase to study the extent to which pragmatic competence is foundational rather than derived from our linguistic abilities.
The evolutionary roots of goal-directed mechanisms: A communication account
Authors: Arnaud Badets
Journal: Behavioral and Brain Sciences (2023)

Unleashed expressions for cooperation are mainly based on the expected perceptual effects of behaviours and not the behaviours themselves. From an evolutionary viewpoint, this goal-directed mechanism allows for a comprehensive story for the theory proposed by Heintz & Scott-Phillips. Over the past 2 million years, this situated mechanism has been reused for tool use and the language development for hominids.
Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation
Authors: Jaslyn Johnson, Yijun Yang, Zilin Bian, Giana Schena, Yijia Li, Xiaoying Zhang, Deborah M. Eaton, Polina Gross, Alexandra Angheloiu, Arshadullah Shaik, Michael Foster, Remus Berretta, Hajime Kubo, Sadia Mohsin, Ying Tian, Steven R. Houser
Journal: Circulation Research (2023)

A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice.
Increased reporting of cerebrovascular accidents with use of risankizumab observed in the Food and Drug Administration Adverse Events Reporting System (FAERS)
Authors: Alexander Egeberg, Jacob P Thyssen
Journal: British Journal of Dermatology (2023)

Recent observational data have suggested an increased risk of cerebrovascular accidents associated with exposure to risankizumab. This article discusses these findings and highlights why there is a need for future observational studies investigating this potential signal.
Expression unleashed in artificial intelligence
Authors: Ekaterina I Tolstaya, Abhinav Gupta, Edward Hughes
Journal: Behavioral and Brain Sciences (2023)

Abstract The problem of generating generally capable agents is an important frontier in artificial intelligence (AI) research. Such agents may demonstrate open-ended, versatile, and diverse modes of expression, similar to humans. We interpret the work of Heintz &amp; Scott-Phillips as a minimal sufficient set of socio-cognitive biases for the emergence of generally expressive AI, separate yet complementary to existing algorithms.
From the pragmatics of charades to the creation of language
Authors: Nick Chater, Morten H. Christiansen
Journal: Behavioral and Brain Sciences (2023)

Abstract We agree with Heintz &amp; Scott-Phillips that pragmatics does not supplement, but is prior to and underpins, language. Indeed, human non-linguistic communication is astonishingly rich, flexible, and subtle, as we illustrate through the game of charades, where people improvise communicative signals when linguistic channels are blocked. The route from non-linguistic charade-like communication to combinatorial language involves (1) local processes of conventionalization and grammaticalization and (2) spontaneous order arising from mutual constraints between different communicative signals.
Increased 18F-Fluoroestradiol Uptake of Radiation Pneumonitis in a Patient With Metastatic Breast Cancer
Authors: Bo Pan, Zhixin Hao, Yidong Zhou, Qiang Sun, Li Huo
Journal: Clinical Nuclear Medicine (2023)

A 42-year-old woman diagnosed with de-novo stage IV breast cancer underwent 18 F-fluoroestradiol (FES) PET/CT to evaluate the estrogen receptor status of metastatic lesions. The largest pulmonary nodule showed obvious FES uptake, consistent with pulmonary metastases from breast cancer. Interestingly, the images revealed a striking accumulation of FES in ground-glass attenuation in the left lobe of lung, suggestive of radiation pneumonitis.
Being ostensive (reply to commentaries on “Expression unleashed”)
Authors: Christophe Heintz, Thom Scott-Phillips
Journal: Behavioral and Brain Sciences (2023)

Abstract One of our main goals with “Expression unleashed” was to highlight the distinctive, ostensive nature of human communication, and the many roles that ostension can play in human behavior and society. The commentaries we received forced us to be more precise about several aspects of this thesis. At the same time, no commentary challenged the central idea that the manifest diversity of human expression is underpinned by a common cognitive unity. Our reply is organized around six issues: (1) languages and their cultural evolution; (2) the pervasiveness of expression in human behavior; (3) artificial intelligence and ostensive communication; (4) communication in other animals; (5) the ecology and evolution of ostensive communication; and (6) biolinguistics and pragmatics.
A commentary on ‘Self-expanding metal ureteral stent for ureteral stricture: experience of a large-scale prospective study from a high-volume center–cross-sectional study’ (Int J Surg 2021; 95: 106161)
Authors: Zhiyong Tan, Shi Fu, Jieming Zuo, Haifeng Wang, Jiansong Wang
Journal: International Journal of Surgery (2023)
Solitary Malignant Peripheral Nerve Sheath Tumor of Lumbar Vertebra Mimicking Metastatic Malignancy
Authors: Ziyu Guo, Wei Liu, Ziqian Dong, Lan Yang, Peng Xie
Journal: Clinical Nuclear Medicine (2023)

Malignant peripheral nerve sheath tumor involving solitary lumbar vertebra is extremely rare. A 72-year-old man had a chief complaint of growing lumbocrural pain for 2 months. The CT scan detected a solitary vertebral lesion, which highly supported the diagnosis of metastatic malignancy. 18 F-FDG PET/CT demonstrated that the vertebral lesion had heterogeneous intense FDG accumulation with an SUV max of 16.4. The pathological examination confirmed the diagnosis of malignant peripheral nerve sheath tumor. This case highlights that MPNST should be considered when there is solitary vertebra invasion with increased FDG uptake.
Structuring unleashed expression: Developmental foundations of human communication
Authors: Wiktor Rorot, Katarzyna Skowrońska, Ewa Nagórska, Konrad Zieliński, Julian Zubek, Joanna Rączaszek-Leonardi
Journal: Behavioral and Brain Sciences (2023)

The target article highlights the sources of open-endedness of human communication. However, the authors' perspective does not account for the structure of particular communication systems. To this end, we extend the authors' perspective, in the spirit of evolutionary extended synthesis, with a detailed account of the sources of constraints imposed upon expression in the course of child development.
P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases
Authors: Jun Zhang, Zhuwan Lyu, Bo Li, Zhengrui You, Nana Cui, You Li, Yikang Li, Bingyuan Huang, Ruiling Chen, Yong Chen, Yanshen Peng, Jingyuan Fang, Qixia Wang, Qi Miao, Ruqi Tang, M. Eric Gershwin, Min Lian, Xiao Xiao, Xiong Ma
Journal: Hepatology (2023)

Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. Methods: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. Results: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. Conclusions: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.
68Ga-FAPI Versus 18F-FDG PET/CT in the Evaluation of Epithelioid Hemangioendothelioma of Bone
Authors: Weizhi Xu, Jiayu Cai, Tinghua Meng, YiZhen Pang, Haojun Chen
Journal: Clinical Nuclear Medicine (2023)

Abstract Epithelioid hemangioendothelioma (EHE) is a rare type of vascular tumor that may arise in bone. Here we presented a 62-year-old man with suspected bone metastases who underwent PET/CT to detect the primary tumor. He underwent 18 F-FDG and 68 Ga-FAPI PET/CT under the prospective trial NCT04416165. Radiotracer uptake was much higher with 68 Ga-FAPI PET/CT than with 18 F-FDG PET/CT in most of bone lesions. No intense uptake likely presenting the primary tumor was observed. Subsequent bone biopsy confirmed the diagnosis of EHE of bone. This case suggested that 68 Ga-FAPI PET/CT might be a useful tool for evaluation of EHE.
Centrosomal microtubule nucleation regulates radial migration of projection neurons independently of polarization in the developing brain
Authors: Stanislav Vinopal, Sebastian Dupraz, Eissa Alfadil, Thorben Pietralla, Shweta Bendre, Michael Stiess, Sven Falk, Germán Camargo Ortega, Nicola Maghelli, Iva M. Tolić, Jiří Smejkal, Magdalena Götz, Frank Bradke
Journal: Neuron (2023)

Cortical projection neurons polarize and form an axon while migrating radially. Even though these dynamic processes are closely interwoven, they are regulated separately-the neurons terminate their migration when reaching their destination, the cortical plate, but continue to grow their axons. Here, we show that in rodents, the centrosome distinguishes these processes. Newly developed molecular tools modulating centrosomal microtubule nucleation combined with in vivo imaging uncovered that dysregulation of centrosomal microtubule nucleation abrogated radial migration without affecting axon formation. Tightly regulated centrosomal microtubule nucleation was required for periodic formation of the cytoplasmic dilation at the leading process, which is essential for radial migration. The microtubule nucleating factor γ-tubulin decreased at neuronal centrosomes during the migratory phase. As distinct microtubule networks drive neuronal polarization and radial migration, this provides insight into how neuronal migratory defects occur without largely affecting axonal tracts in human developmental cortical dysgeneses, caused by mutations in γ-tubulin.
Prolonged administration of a secretin receptor antagonist inhibits biliary senescence and liver fibrosis in Mdr2−/− mice
Authors: Nan Wu, Tianhao Zhou, Guido Carpino, Leonardo Baiocchi, Konstantina Kyritsi, Lindsey Kennedy, Ludovica Ceci, Lixian Chen, Chaodong Wu, Debjyoti Kundu, Nipuni Barupala, Antonio Franchitto, Paolo Onori, Burcin Ekser, Eugenio Gaudio, Heather Francis, Shannon Glaser, Gianfranco Alpini
Journal: Hepatology (2023)

Background and Aims: Secretin (SCT) and secretin receptor (SR, only expressed on cholangiocytes within the liver) play key roles in modulating liver phenotypes. Forkhead box A2 (FoxA2) is required for normal bile duct homeostasis by preventing the excess of cholangiocyte proliferation. Short-term administration of the SR antagonist (SCT 5–27) decreased ductular reaction and liver fibrosis in bile duct ligated and Mdr2 −/− [primary sclerosing cholangitis (PSC), model] mice. We aimed to evaluate the effectiveness and risks of long-term SCT 5–27 treatment in Mdr2 −/− mice. Approach and Results: In vivo studies were performed in male wild-type and Mdr2 −/− mice treated with saline or SCT 5–27 for 3 months and human samples from late-stage PSC patients and healthy controls. Compared with controls, biliary SCT/SR expression and SCT serum levels increased in Mdr2 −/− mice and late-stage PSC patients. There was a significant increase in ductular reaction, biliary senescence, liver inflammation, angiogenesis, fibrosis, biliary expression of TGF-β1/VEGF-A axis, and biliary phosphorylation of protein kinase A and ERK1/2 in Mdr2 −/− mice. The biliary expression of miR-125b and FoxA2 decreased in Mdr2 −/− compared with wild-type mice, which was reversed by long-term SCT 5–27 treatment. In vitro , SCT 5–27 treatment of a human biliary PSC cell line decreased proliferation and senescence and SR/TGF-β1/VEGF-A axis but increased the expression of miR-125b and FoxA2. Downregulation of FoxA2 prevented SCT 5–27–induced reduction in biliary damage, whereas overexpression of FoxA2 reduced proliferation and senescence in the human PSC cell line. Conclusions: Modulating the SCT/SR axis may be critical for managing PSC.
Covid-19 should prompt us to rethink how and where care is best delivered
Authors: Charlotte Grinberg, Lois Quam
Journal: BMJ (2023)

Amid the crisis of war, Florence Nightingale, the mother of modern nursing, reorganised where and how medical care was provided.More wounded soldiers survived and the lessons that were learnt transformed nursing care.Now in the wake of the global covid-19 pandemic, we have a similar opportunity to use what we've learnt to improve patient outcomes, deliver care in more convenient settings, and support caregivers.
When I use a word . . . . Language games
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

The idea of language games was propounded by Ludwig Wittgenstein. He expounded the philosophical position that the meaning of a word is specific to its context and that a word may have different meanings depending on the context—or the language game—in which it is used and that usage therefore is an important determinant of meaning. Deciding what a word actually means, how to use it, how to pronounce it, and sometimes even how to spell it, depends on the language game in which it is used. Analysis of medical terminology can be facilitated by considering etymology, grammar, and usage, and sometimes by taking a historical perspective or even occasionally considering the effect a particular usage may have on patient care.